1. Technical Field
The present invention relates to compositions for prevention, treatment, and diagnosis of chronic obstructive pulmonary disease (COPD).
2. Background Art
Chronic obstructive pulmonary disease (COPD) is currently defined as chronic disease showing irreversible obstruction of airways resulting from the progression of two major underlying diseases including chronic bronchitis and pulmonary emphysema. Chronic bronchitis is defined clinically as the persistence of cough, sputum, and difficult breathing, and pulmonary emphysema is defined histopathologically as an irreversible destruction of airway walls distal to the terminal bronchiole and clinically shows slowly progressive respiratory difficulties (GOLD workshop summary, Am J Respir Crit. Care Med 2001; 163:1256-1276). Therefore, current definition of COPD excludes a bronchial asthma showing reversible obstruction of airways. COPD is currently the fourth leading cause of death in the United States and Europe, and causes of death in patients with COPD are complications of the disease such as respiratory failure or infection (GOLD workshop summary, Am J Respir Crit. Care Med 2001; 163:1256-1276).
Currently, smoking is regarded as the most important risk factor for the development of COPD. And secretions of many inflammatory mediators (IL-8 etc.) from airway epithelial cells stimulated by smoking and other factors including air pollution or chronic infection by bacteria or virus are considered to be responsible for the development of chronic inflammation of airway tissue in COPD (GOLD workshop summary, Am J Respir Crit. Care Med 2001; 163:1256-1276). However, the reason for the chronic persistence of inflammation after acute inflammation induced by those external stimuli is not determined yet. Accordingly, it is suggested that other pathogenetic mechanisms besides smoking may be involved in the pathogenetic mechanism of COPD (O'Byrne P M, Postma D S. Am J Respir Crit. Care Med 1999; 159:S41-S66). Especially, the reasons for the persistence of airway inflammation and apoptosis of airway epithelial cells in COPD patients even after stop of smoking are not explained yet (Hodge S et al., Eur Respir J 2005; 25:447-54). The etiology and pathogenetic mechanism of COPD are not determined yet, and therefore, fundamental treatment of COPD is difficult now. The COPD patients having advanced disease and severely decreased pulmonary function are at a high risk of the disease-associated premature death (GOLD workshop summary, Am J Respir Crit. Care Med 2001; 163:1256-1276).
Currently, diagnosis of chronic obstructive pulmonary disease can be made when the patients complain of typical clinical symptoms (cough, sputum, and dyspnea, etc.) and their FEV1 measured following the inhalation of bronchodilator showed less than 80% of predictive value and the ratio of FEV1/FVC was less than 70% on pulmonary function test (GOLD workshop summary, Am J Respir Crit. Care Med 2001; 163:1256-1276). However, there is still no laboratory test which can be used for the early detection of patients with COPD who complain of typical clinical symptoms but show normal pulmonary function and thereby used for the prevention of further progression of COPD.
As a pharmacological therapy of COPD, bronchodilator and corticosteroid are known to be effective for the improvement of clinical symptoms. Direct administration of corticosteroid to the target airway tissue by inhalation devices is preferred method over systemic administration to avoid systemic side effects. Additional medications such as theophylline can also be useful. However, there is still no available therapeutic agent which can induce complete remission of COPD or fundamentally improve COPD and modify a natural course of the disease.
Detection of autoantibodies to antigens of airway or lung tissues in COPD patients has been reported (Wagner V, et al., Acta Allergol 1965; 20:1-9). Although a hypothesis that COPD is caused by autoimmune mechanism has been proposed (Agusti A, et al., Thorax 2003; 58:832-834), this hypothesis has not been clearly demonstrated because an autoantigen reacting with autoantibodies in the blood of patients with COPD has not been identified yet. Recently, it has been demonstrated that pulmonary emphysema (one of major underlying diseases causing COPD) could have been developed in animals by autoimmune response against the vascular endothelial autoantigen (Taraseviciene-Stewart L, et al., Am J Respir Crit. Care Med. 2005; 171:734-42). In the above study, it has been reported that rats immunized by antigens extracted from human vascular endothelial cells to induce autoimmune response developed pulmonary emphysema, and passive transfer of CD4+ cells from spleens of the above pulmonary emphysema-developed rats to naive rats resulted in pulmonary emphysema in recipient rats, and pulmonary emphysema has been also caused in mouse after injection of anti-endothelial cell antibodies obtained from serum of rats immunized with vascular endothelial cells (Taraseviciene-Stewart L, et al., Am J Respir Crit. Care Med. 2005; 171:734-42). This study showed that antibodies to vascular endothelial cell antigens were sufficient to trigger the development of pulmonary emphysema, although target autoantigens involved in development of the disease was not identified yet. On the basis of above, it has been suggested that autoimmune mechanism might be involved in the pathogenesis of COPD.